1. Technical Field
This invention relates generally to diarylmethylpiperazine compounds useful as mu and/or delta receptor opioid compounds and pharmaceuticals containing same that may be useful for mediating analgesia, combating drug addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, lung edema, diarrhea, cardiac disorders, cardioprotection, depression, and cognitive, respiratory, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, and anti-tumor agents.
2. Background of Related Art
In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds have been identified. In this effort, significant research has been focused on understanding the mechanism of opioid drug action, particularly as it relates to cellular and differentiated tissue opiate receptors.
Opioid drugs typically are classified by their binding selectivity in respect of the cellular and differentiated tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (μ), delta (δ), sigma (σ) and kappa (κ) receptors.
The well-known narcotic opiates, such as morphine and its analogs, are selective for the opiate mu receptor. Mu receptors mediate analgesia, respiratory depression, and inhibition of gastrointestinal transit. Kappa receptors mediate analgesia and sedation. Sigma receptors mediate various biological activities.
The existence of the opioid delta receptor is a relatively recent discovery that followed the isolation and characterization of endogenous enkephalin peptides that are ligands for the delta receptor. Delta receptors mediate analgesia, but do not appear to inhibit intestinal transit in the manner characteristic of mu receptors.
Opioid agents frequently are characterized as either agonists or antagonists. Agonists and antagonists are agents that recognize and bind to receptors, affecting (either initiating or blocking) biochemical/physiological sequences, a process known as transduction. Agonists inhibit or suppress neurotransmitter outputs in tissues containing receptors, e.g., inhibiting pain responses, or affecting other output-related phenomena. Antagonists also bind to receptors, but do not inhibit neurotransmitter outputs. Thus, antagonists bind to the receptor sites and block the binding of agonist species that are selective for the same receptor.
Various physiological effects of the known peptide-based opioid ligands have been studied, including: analgesia; respiratory depression; gastrointestinal effects; mental, emotional, and cognitive process function; and mediation/modulation of other physiological processes.
There is a continuing need in the art for improved opioid compounds, particularly compounds that are free of addictive character and other adverse side effects of conventional opiates such as morphine.
Previous disclosed diarylmethylpiperazine compounds exhibiting delta receptor agonist activities produced seizure-like convulsion activity in mice and rats after a rapid bolus iv administration through central (central nervous system, CNS) mechanism. Similarly, these compounds including current therapeutic analgesics possessing mu opioid receptor agonist activity produce respiratory depressive, nausea and emesis effects, addictive effects and abuse liability through a central mechanism. Delta and mu opioid receptors are localized in peripheral organs and tissues. Various physiological effects are known for those peripheral organs and tissues: gastro-intestinal tracts disorder such as antidiarrhea, and irritable bowl syndrome, cough, bladder functional modulation, genital organ regulation such as vas deferens contractility, immuno-modulation, and cardioprotection for heart attack. For those peripheral applications, compounds that lack central side effects are desirable.
The present invention described a series of novel opioid compounds, with potent delta and/or mu receptor agonist activities, that produce essentially no central mechanism side effects as evident from the lack of centrally mediated seizure-like convulsion activity and antinociception in tail-pinch assay after a rapid bolus iv injection of a high dose in mice.